Cow's milk allergy (CMA) affects approximately 2.5% of all infants and is considered the most common food allergy in this age group [Sicherer S H et al. (2010), Food allergy, Sampson H A, J. Allergy Clin. Immunol. (125)]. Approximately 85% of children out-grow their allergy to cow's milk before the age of 2 to 3 years old. As such, CMA affects other age groups with a lower prevalence.
The allergies to cow's milk and to the formulas containing cow's milk adapted to the needs of infants are due to the fact that the proteins of cow's milk differ from the proteins of mother's milk and can constitute allergens.
Besides breastfeeding, the primary recommendation for prevention of CMA is the use of partially hydrolyzed hypoallergenic formulae, which are recommended to be prescribed to “at risk” asymptomatic infants, with atopic parents.
In contrast to standard infant cow's milk formulae, in hypoallergenic formulae, the cow's milk proteins have been hydrolyzed, to decrease their potential allergenicity. This approach has been demonstrated to be efficient to prevent sensitization by native (full length) proteins present (albeit in a much lower quantity than that in a non-hydrolyzed formula) in the formulae.
Hydrolysates may be characterized as “partial” or “extensive” depending on the degree to which the hydrolysis reaction is carried out. Currently, there is no agreed legal/clinical definition of Extensively Hydrolyzed Products according to the WAO (World Allergy Organization) guidelines for CMA, but there is agreement that according to the WAO hydrolyzed formulas have proven to be a useful and widely used protein source for infants suffering from CMA. In the current invention a partial hydrolysate is one in which 60% of the protein/peptide population has a molecular weight of less than 1000 Daltons, whereas an extensive hydrolysate is one in which at least 95% of the protein/peptide population has a molecular weight of less than 1000 Daltons. These definitions are currently used in the industry.
There are currently many examples of casein or whey-based hypoallergenic partially or extensively hydrolyzed formulae (e.g. NAN-HA™, also known as BEBA-HA™, Alfare™, Altéra™ from Nestlé, and S26-HA™ from Pfizer) on the market.
For infants already displaying symptoms of CMA, non-allergenic milk substitute formulae, such as free amino acids (e.g. Vivonex™ from Nestlé) or soy based formulas (such as S-26 Soy™, NURSOY™ from Pfizer, New York, and NESTLÉ® Good Start® ALSOY® from Nestlé) may be suitable alternatives to cow's milk standard or hypoallergenic formulae.
Thus, the primary focus to date in providing nutrition for children with allergies to cow's milk has been to find preparations which will not induce an allergic response, i.e. to provide non-allergenic formulations. One of the drawbacks of administering non-allergenic formulae (containing either free amino acids, soya based milk or extensively hydrolyzed cow's milk proteins) to infants is that, while such formulations allow infants who are allergic to cow's milk to avoid an allergic response, they do not allow those children to develop oral tolerance to the cow's milk protein allergens so that they can go on to drink unaltered milk products later in life.
Oral tolerance is the specific suppression of cellular and/or humoral immune reactivity to an antigen by prior administration of the antigen by the oral route. It is an important part of the development of the immune system in the first months of life and allows the infant to consume food without adverse reaction. Failure of the establishment of oral tolerance leads to allergy. The development of oral tolerance is linked to the normal immune system education, resulting in a reduced reaction to food antigens.
Several factors have been identified as affecting the induction and maintenance of oral tolerance, among these, the structure of the food protein, the dose and frequency of the antigen administration, as well as the immune status of the host.
It is believed that some peptides, that may be specifically present in partially hydrolyzed infant formula, have the ability to interact with the immune system and induce oral tolerance.
It has been found that partially hydrolyzed milk formulations are not only of reduced allergenicity but can induce immunological tolerance to milk proteins (EP 0827 679).
Thus, European patent application EP 2 332 428 discloses a formulation comprising a cow's milk peptide-containing hydrolysate capable of inducing oral tolerance. The peptides in question were identified as coming from bovine casein.
WO 00/42863 describes the identification of a number of tolerogenic peptides of β-lactoglobulin (one of the major cow's milk allergens) capable of inducing oral tolerance, as evidenced by reduced immune responses (IgE) to the native protein in mice previously exposed to the peptides in question, compared to mice that had not been exposed to the peptides. In that patent application, the authors refer to EP 0 629 350, which discloses the use of non-allergenic whey protein hydrolysates which are said to be capable of inducing cow's milk protein tolerance. The authors of WO 00/42863 indicate that although in EP 0 629 350 it was stated that whey protein hydrolysates substantially free of allergenic proteins could be used to induce cow's milk protein tolerance in children at risk of cow's milk allergy, they found, on analyzing other non-allergenic whey protein hydrolysates, that non-allergenicity did not necessarily translate into the ability to induce cow's milk protein tolerance. They went on to say that even some of the formulations exhibiting the highest degree of non-allergenicity were found to be unsuitable for inducing cow's milk protein tolerance.
Furthermore, it is known that extensively hydrolyzed formulae lose their ability to induce long-term oral tolerance, i.e. the hydrolysis modifies extensively the nature of the protein in a way that it is no longer recognized by the immune system. This leads to the loss of a critical benefit.
Thus, there is a need to further identify the factors that may influence induction of oral tolerance. It is highly desirable to provide hypoallergenic or non-allergenic compositions to be used as a complement to or substitute for breast milk and having an ability to induce oral tolerance in the infant.
There is a need to provide synthetic nutritional solutions that can alleviate the development of allergies, especially in infants. There is a need to induce tolerance to a variety of allergens including milk allergens and milk proteins.
There is a need to design and produce nutritional interventions, especially via synthetic ingredients or combinations of ingredient, that can be administered to infants early in life and that reduce the probability or the magnitude of being or becoming allergic or developing allergies later in life.
This need exists for the general population of infants and also for sub-populations of infants having predisposition to allergies or having declared allergies.
There is a general need to provide relief from allergies or allergy symptoms and to develop means of inducing the tolerance to common allergens, such as milk allergens, especially in children and infants.